The importance of orthopedic substitutes is underscored by the fact that the World Health Authority has decreed 2000-2010 the Bone and Joint Decade. Bone substitutes are the most common implanted materials, and are second only to transfused blood products as products delivered internally. Bone substitutes are used to help repair or replace skeletal deficiencies resulting from trauma, tumors, surgery, congenital and degenerative diseases or abnormal development.
Current methods for the repair of bony defects include autografting and allografting. Autologous bone grafts utilize cortical and cancellous bone that is harvested and transplanted within the same patient. Autologous bone grafting is currently the most effective procedure for repair of bony defects, and is the standard against which all other methods are judged. The advantages of autologous bone grafts include their excellent success rate, low risk of transmitting disease, and histocompatibility. Allografts utilize bone harvested from a different organism of the same species, and lack the osteogenic properties of autografts. Their healing capacity is consequently lower. Allografting also carries a risk of transmitting certain diseases, and may elicit intense immunological reactions. Although both autologous and allogenic grafts can be used successfully, they suffer from problems associated with harvesting costs, limited availability, and donor site morbidity.
Purified and synthetic materials, including metals, plastics, ceramics, and collagen-based matrices have been developed as bone substitutes in an attempt to obviate these problems. These materials can be produced in large quantities and in a variety of shapes and sizes, and most are non-immunogenic. However, metals and plastics, which were the first synthetic materials to be used clinically, are subject to fatigue, fracture, and wear, and do not remodel or resorb with time. More recently, the FDA has approved a coral derived hydroxyapatite for use in contained bone defects, and a purified collagen/ceramic composite material for use in acute long bone fractures. Although these materials avoid the morbidity involved in harvesting bone and eliminate the problems associated with limited donor bone availability, they are much less effective than autografts. This explains, at least partly, the fact that in 2000 synthetic bone substitutes represented less than 15% of the global use of bone grafts.
There is, therefore, a continued interest in the development of new, improved bone graft materials. Knowledge of the structure and mechanical properties of bone and a better understanding of the natural bone healing process have allowed investigators to define desirable characteristics of a successful implant material. Bone substitutes should desirably be biocompatible, osteoconductive, integrative and mechanically compatible with native bone. Materials that are osteoinductive are particularly desirable. These materials should provide cell anchorage sites, mechanical stability and structural guidance, and serve as a source of osteogenesis over the time period required for bone replacement.
Since the biological and mechanical properties of bone result from its microstructural features, a strategy in the development of the ideal substitute material is to mimic the structure of natural bone. Bone is a composite material made up of organic and inorganic components, where the inorganic or mineral phase represents 60-70% of the total dry bone weight. The organic phase is a viscous gel-like material comprised primarily of type I collagen while the mineral component consists of a crystalline form of calcium phosphate containing carbonate ions, small amounts of sodium, magnesium, hydrogenophosphate ions and other trace elements. The interaction of the hard brittle mineral phase and the flexible organic matrix gives bone its unique mechanical properties. The ability of bone to perpetually remodel is ascribed, at least in part, to the calcium phosphate ratio of the mineral phase as well as to the particular crystalline nature of bone. A sound approach in developing a bone substitute is therefore to combine minerals to an organic polymeric matrix to generate a composite material exhibiting the toughness and flexibility of the polymer and the strength and hardness of the mineral filler.
In recent years, several of these composites have been designed and developed, with powders or ceramics of calcium phosphate (the main bone mineral component) acting as inorganic fillers. Among the calcium phosphate ceramics, hydroxyapatite and tricalcium phosphate ceramics are the most commonly used. Calcium phosphate-based composites possess unique advantages over their constituents, combining the osteoconductivity of the mineral with the easy processing of polymers. In addition, by taking advantage of the wide range of properties of polymers, composites can be made to meet the needs of a large variety of clinical applications. Numerous patents disclose the preparation and composition of such bone substitutes made of calcium phosphate and natural (U.S. Pat. Nos. 4,516,276; 4,776,890; 5,626,861; 6,201,039; and 6,395,036) or synthetic (U.S. Pat. Nos. 4,192,021; 4,263,185; 4,187,852; and 5,338,772) polymers.
Another series of composites, based on the use of bone particles as mineral fillers, has also been developed. Most of these composite materials are prepared from demineralized bone (from human or animal origin) and biocompatible polymers (see, for example, U.S. Pat. Nos. 4,394,370; 4,440,750; 4,863,732; and 5,531,791). The demineralization process is carried out to totally or partially remove minerals and better expose the bone collagen in order to favor the binding of the bone particles to the organic polymer matrix. The resulting compositions can be delivered in a fluid or gel state, they promote cellular infiltration from adjacent osseous tissues, and may possess osteoinductive and osteoconductive properties. Implantable sponges, bandages or prostheses have been formed from these demineralized bone/collagen composites (U.S. Pat. No. 4,394,370).
However, demineralized materials are rarely employed as load-bearing bone products, which are used at implant sites where the bone graft is expected to withstand some level of physical load. Several attempts have been made to produce materials with mechanical properties as close as possible to those of natural bone. Some preparation methods disclose removing all organic material from bone to yield bone mineral by pyrolytic or chemical processes (U.S. Pat. No. 4,882,149) or by using a fluid in the supercritical state (U.S. Pat. No. 6,217,614). Other procedures advocate the removal of only part of the organic component (in U.S. Pat. No. 6,261,586, for example, the bone material is processed to remove associated non-collagenous bone proteins but naturally associated native collagen materials and bone minerals are preserved). Composites have been formed by combination of these nondemineralized bone materials with natural polymers, such as collagen and gelatin (U.S. Pat. Nos. 4,314,380 and 5,573,771) and synthetic polymers, such as lactic polyester (U.S. Pat. No. 5,573,771). Most of these products are intended to be used as remodeling implants, vertebral spacers or prosthetic bone replacements.
Although the composite materials described above have led to the production of biocompatible load-bearing implants with attractive characteristics, they are still in need of improvement. Actually, none of the calcium phosphate-based composites have been shown to possess in vivo mechanical properties comparable to those of natural bone and in most cases, the same is true for the bone-composite materials. In general, these composites exhibit a poor polymer/filler interface [Reis et al. “Structure development and control of injection-moulded hydroxyapatite-reinforced starch/EVOH composites” Adv. Polym. Tech. 16:263-277 (1997)]. In the absence of a good interfacial adhesion between the organic polymer and the mineral filler, transfer of the stresses experienced by the load-bearing implant from the “soft” polymer to the “hard” filler is difficult. A lack of adhesion between the two phases results in early failure. In the case of industrial composites, the compatibility between the filler and the polymer has long been known to improve by using several types of surface coatings, coupling agents, or other additives.
In the field of biomaterials, similar methods have recently been applied to improve the interface of hydroxyapatite/polymer composites using coupling agents [Nishizawa et al. “Surface modification of calcium phosphate ceramics with silane coupling agents” Chem. Soc. Jpn. 1:63-67 (1995); Dupraz et al. “Characterization of silane-treated hydroxyapatite powders for use as filler in biodegradable composites” J. Biomed. Mater. Res. 30:231-238 (1996)]; zirconium salts [Misra, “Adsorption of zirconium salts and their acids in hydroxyapatite: The use of salts as coupling agents to dental polymer composites” J. Dent. Res. 12:1405-1408 (1985)]; and polyacids [Liu et al. “Surface modification of hydroxyapatite to introduce interfacial bonding with Polyactive™ 70/30 in a biodegradable composite” J. Mater. Sci. Mater. Med. 7:551-557 (1996); and Liu et al. “Polyacids as bonding agents in hydroxyapatite/polyester-ether Polyactive™ 30/70 composites” J. Mater. Sci. Mater. Med. 9:23-30 (1998)]. For the same purpose, hydroxyethyl methacrylate has been chemically coupled to octocalcium phosphate [Delpech et al. “Calcium phosphate and interfaces in orthopedic cements” Clin. Mater. 5:209-216 (1990); and Dandurand et al. “Study of the mineral-organic linkage in an apatitic-reinforced bone cement” J. Biomed. Mater. Res. 24:1377-1384 (1990)], and polyethylene glycol has been grafted to the surface of nano-apatite [Liu et al. “Covalent bonding of PMMA, PBMA, and poly(HEMA) to hydroxyapatite particles” J. Biomed. Mater. Res. 40: 257-263 (1998)]. U.S. Pat. No. 6,399,693 discloses a composite material comprising a mixture of silane functionalized polyaromatic polymer and an organic or inorganic material containing moieties reactive with the silane groups. In most cases, these treatments result in significant improvements in the ultimate stiffness of the composite. However, one major drawback lies in the fact that, in the presence of the different coupling agents and additives, the chemical bonds formed between hydroxyapatite and the polymer matrix are too “permanent” (i.e., they are too strong and too stable to hydrolysis, dissolution, and/or biological/enzymatic attack) thereby inhibiting the remodeling of the grafting material and gradual degradation of the composite.